Demyelination and axonal dystrophy in alpha A-crystallin transgenic mice

Homozygous mice transgenic for alpha A-crystallin, one of the structural ey e lens proteins, developed hindlimb paralysis after 8 weeks of age. To unra vel the pathogenesis of this unexpected finding and the possible role of al pha A-crystallin in this pathological process, mice were subjected to a his topathological and immunohistochemical investigation. Immunohistochemistry showed large deposits of alpha A-crystallin in the astrocytes of the spinal cord, and in the Schwann cells of dorsal roots and sciatic nerves. Additio nally, microscopy showed dystrophic axons in the spinal cord and digestion chambers as a sign of ongoing demyelination in dorsal roots and sciatic ner ves. Apart from a few areas with slight alpha A-crystallin-immunopositive s tructures, the brain was normal. Because the alpha A-crystallin protein exp ression appeared in specific cells of the nervous system (astrocytes and Sc hwann cells), the most plausible explanation for the paralysis is a disturb ance of cell function caused by the excessive intracytoplasmic accumulation of the alpha A-crystallin protein. This is followed by a sequence of secon dary changes (demyelination, axonal dystrophy) and finally arthrosis. In co nclusion, alpha A-crystallin transgenic mice develop a peripheral and centr al neuropathy primarily affecting spinal cord areas at the dorsal side, dor sal root and sciatic nerve.